Substituted 6-amino alkyleneoxy 3, 5-cycloandrostanes



United States Patent This invention relates to new steroid compounds.More particularly, it relates to 3,5-cycloandrostanes and methods ofpreparing the same.

The new steroids of the present invention may be illustrated by thefollowing structural formula:

CH CH3 011 wherein R and R are lower alkyl radicals, n is an integer of2 to 4 and C is selected from the group consisting of CH 9 0, C=NOH andC=NO-lower alkyl and Cl-IOH. The present compounds also form hydrohalidesalts which areincluded within the scope of the present invention.

The compounds of this invention are, in general, white crystallinesolids, relatively insoluble in water but soluble in lower alkanols,ethyl acetate, acetone, tetrahydrofuran, methylene'chloride and thelike.

The compounds of the present invention are prepared using as startingmaterial dehydroisonandrosterone which is reacted with p-toluenesulfonylchloride to produce dehydroisoandrosterone' ptoluenesulfonate.. Thelatter compound when heated with potassium acetate in a solvent, such asfor example, aqueous acetone give 3,5- cycloandr0stan-6fi-ol-l7-one. Onheating the latter compound with hydrazine hydrate and. potassiumhydroxide in a solvent such as diethylene glycol 3,5-cycloandr0stan-'6i-It-ol is obtained. On heating the latter in the presence of potassiumt-butoxide with diethylaminoethyl chloride in a solvent 69-(,8-diethylaminoethoxy)-3 ,5-cycloandro- .stane is obtained. a

The compounds of the present invention such as 6,8- (B-di-loweralkylaminoethoxy)-3,5-cycloandrostan-l7-one can he prepared by heatingfor example 3fi-p-toluenesulfonyloxyandrost--en-17-one in dioxane withfused potassium acetate and a Z-alkylaminoethanoL- The lat-' one withmethoxyamine hydrochloride under alkaline conditions. Thehydrohalide-salts of the latter compounds may be prepared by treatmentwith, for example, hydrogen chloride which produces the hydrochloridesalt.

3,185,715 Patented May 25, 1965 See l7-one are useful in treatinghypercholesteremia. The present compounds can be incorporated withfillers, excipients, flavors, etc. and compounded into tablets,capsules, pills and other well known pharmaceutical forms.

The following examples illustrate in detail the preparation ofrepresentative compounds of the present invention.

EXAMPLE 1 Dehydroisoandrosterone p-toluenesulfonate To a solutioncontaining g. of dehydroisoandrosterone in 400 ml. of pyridine is added39.6 g. of p-toluenesulfonyl chloride. After about 24 hours, thereaction mixture is poured into 1.5 liters of ice water. The product isextracted into methylene chloride and the combined extract is washedsuccessively With diluted hydrochloric acid, water, 5% sodiumbicarbonate, water and saturated sodium chloride solution. It is driedover anhydrous sodium sulfate and evaporated to a viscous oil whichcrystallizes from acetone-petroleum ether to give 49.3 g. (80%), meltingpoint ISO-151 C. with decomposition.

EXAMPLE 2 3,5-cycloandrostan-dfl-ol-l 7 -one A mixture composed of 49.0g. of dehydroisoandrosterone p-toluenesulfonate and 54.4 g. of potassiumacetate in 3 liters of aqueous acetone is heated to reflux for 17 hours.The mixture is concentrated to about 2 liters, diluted with water andextracted repeatedly with ether. The combined extract is washed withwater and saturated sodium chloride solution and evaporated to a solidmass. The latter is crystallized from acetone-petroleum ether to give23.4 g. (74%), melting point 134- 140 C. One recrystallization from thesame solvents gives 21.8 g, melting point 139-141.5 C., [a] +120 Thecompounds such as 6fl-(fl-di-lower alkylaminoexample,6,8-(fi-diethylaminoethoxy)-3,5-cycloandrostan- (EtOl-l) EXAMPLE 3 3,5-cycl0androsta-n-6 ,B0l

A solution composed of 25g. of 3,5-cycloandrostan- 6B-ol-17-one, 23 g.of potassium hydroxide, 20 ml. of hydrazine hydrate and ml. ofdiethylene glycol is heated to reflux for one hour. The reflux condenseris removed and the solution is distilled until its temperature rises to198 C. The condenser is replaced and reflux is continued for 2.5 hours.Upon cooling the mixture is poured into Water, giving a semi-crystallinesolid which is collected by filtration. The latter is dissolved inether, washed with water, dried and evaporated to an oil whichcrystallizes from aqueous methanol to yield 38 g. of Wet solid. Uponvacuum drying at room temperature, the product reverts to an oil. Itsinfrared spectrum (KBr disc) is devoid of any carbonyl absorption and itis employed in Example 4 without purification.

EXAMPLE 4 6p-(B-diethylaminoethoxy)-3,5-cycl0andr0sta'ne Toa solutioncontaining 16 g. of 3,5-cycloandrostandB-.01 in 600 ml. oftetrahydrofuran is added 8 g. of potassium t-butoxide. The resultingmixture is heated to reflux and stirred under a nitrogen atmosphere forone hour. Diethylaminoethyl chloride (28 ml.) is added drop'wise over 2hours to the stirred, refluxing mixture. Potassium t-butoxide (8 g.) isadded and reflux is con- The reaction mixture is cooled, filperature.The oil resolidified upon addition of acetone to give 0.70 g., meltingpoint l91208 C. (dec.),

1118 and. 1032 cmf EXAMPLE 5 6 ,8- [S-diethy lam inoethoxy -3 ,5 -cycloandrostan-J 7 one 1012 and 1022 cmf In the above example, in place ofZ-diethylaminoethanol there may be substituted Z-dirnethylaminoethanol,3-dlethylaminopropanol, and 4-diethylaminobutanol to give respectively6,8-(B-d-imethylaminoethoxy) 3,5 cycloandrosta-n-17-one,6p?-(v-diethylaminopropoxy)-3,5-cycloan- 1drostan-17-one, and6,8-(e-diethylaminobutoxy)-3,5-cycloandrostan-17-one.

EXAMPLE 6 6 6- [i-di ethylaminoethoxy -3,5 -cyclandr0stan-1 76-01 To asolution containing g. of6B-(B-diethylaminoethoxy)-3,5-cycloandrostan-17-one in 100 ml. ofmethanol is added a few drops of 5% potassium hydroxide solution and 5.2g. of sodium borohydride. The resulting solution is stirred at roomtemperature for 45 minutes, diluted with water and placed in arefrigerator to stand overnight. The product of the example is collectedby filtration, washed well with water and dried.

EXAMPLE 7 6 B- B-diethylaminoethoxy -1 7-methoximin0-3,5-

cycloandrostane GB-(fl-diethylaminoethoxy) 3,5 cycloandrostan-17-one(3.0 g.) is dissolved in 60 ml. of ethanol. To the resulting solution isadded 4.8 g. of methoxyamine hydrochloride and a solution containing 3.9g. of potassium hydroxide in 6 ml. of Water. The reaction mixture isheated to reflux for 18 hours, filtered and extracted with ether.Evaporation gives the product of the example.

EXAMPLE 8 6 ,8- fl-diethy laminoetholxy 7-methoximino-3,5-cyclo- Vandrostane hydrochloride 65. (fi-diethylaminoethoxy) -17-methoximino-3,5 -cycloandrostane (2 g.) is dissolved in ether. Hydrogen chloride ispassed into the resulting solutionand the product of the exampleprecipitates and is collected by filtration.

EXAMPLE 9 6,5- B-aiethylaminoethoxy 7-is0ni tr0s0-3 ,5 cycloandrostaneTo a solution containing 2.5 g. of6fi-(p3-diethylaminoethoxy)-3,5-cycloandrostan-17-one in 50 ml. ofethanol is added 4 g. of hydroxylarnine hydrochloride and 3.3 g. ofpotassium hydroxide in 5 ml. of water. The resulting mixture is heatedto reflux for 2 hours, cooled and filtered. The filtrate is concentratedto a small volume, diluted with water and extracted repeatedly withmethylene chloride. The combined extract is Washed with water, driedover anhydrous sodium sulfate and evaporated to give the product of theexample.

We claim: v

l. A compound selected from the'group consisting of a compound of theformula:

CH3 CH3 on 01 7 k7 R No references cited.

LEWIS GOTTS, Primary Examiner,

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA: